A number of prior art references teaches the advantages of delivery of therapeutic agents to the lower part of the gastrointestinal tract, especially the large intestine or the colon. These reference illustrate the difficulty of formulating dosage forms that will achieve this delivery benefit. For example, U.S. Pat. Nos. 5,541,170 and 5,541,171, Rhodes et al., both issued Jul. 30, 1996, discuss the delivery of pharmacologically active agents, especially 5-aminosalicylic acid, to the large intestine for the treatment of colonic or rectal disorders. U.S. Pat. No. 5,686,105, Kelm et al., issued Nov. 11, 1997, teaches colonic delivery of therapeutic agents wherein the dosage form comprises a coating system with at least one inner coating layer and one outer coating layer. The inner coating layer is an enteric polymer that begins to dissolve in an aqueous media at a pH between about 5 to about 6.3, and the outer coating layer is an enteric polymer that begins to dissolve in an aqueous media at a pH of between about 6.8 to 7.2. U.S. Pat. No. 5,171,580, Iamartino et al., issued Dec. 15, 1992, teaches pharmaceutical preparations containing an active ingredient to be released in the lower part of the gastrointestinal tract, the large intestine and especially the colon, consisting of a core with the active, the core being coated with three protective layers at different solubilities. This reference focuses on providing more specific and reliable release of a therapeutic active agent to the lower part of the gastrointestinal tract, especially the colon, achieved with the three protection layers, as well as the benefits of having a selective effect in the colon. Other prior art references also focus on the benefits of delivering therapeutic agents to the colon. These references include U.S. Pat. No. 5,686,106, Kelm et al., issued Nov. 11, 1997; U.S. Pat. No. 5,914,132, Kelm et al, issued Jun. 22, 1999; U.S. Pat. No. 4,910,021. Davis et al, issued Mar. 20, 1990: U.S. Pat. No. 4,432,966, Zeitoun et al., issued Feb. 21, 1984; U.S. Pat. No. 5,654,004, Okayama et al., issued Aug. 5, 1997; U.S. Pat. No. 5,900,252, Calcanchi et al., issued May 4, 1999; U.S. Pat. No. 5,482,718, Shah et al, issued Jan. 9, 1996; U.S. Pat. No. 5,316,772, Jurgens et al., issued May 31, 1994; EP 225,189, Davies, et al, published Jun. 10, 1987; and Khan et al., Drug Development and Industrial Pharmacy, 26(5), 549-554 (2000).
None of the above prior art references, however, discusses the problem or possibility of coating fractures that may occur during processing, manufacturing, or packaging of the oral unit dosage form. Coating fractures may cause unreliable or inconsistent delivery or release of the therapeutic agent to the desired region of the gastrointestinal tract. These fractures may be associated with premature rupture or release of the unit dosage forms. Indeed, coating fractures may especially be problematic for larger than average size unit dosage forms or heavier unit dosage forms resulting from using larger dosages/levels of the therapeutic active.
The present invention, therefore, relates to solid unit dosage forms for oral administration in humans or lower animals which minimizes the impact or negative effects of coating fractures, especially for larger or heavier unit dosage forms. By reducing these negative effects, these compositions maintain the desired site of delivery of the therapeutic agents in the gastrointestinal tract.